The objective of this research program is to define the molecular mechanisms that regulate the inflammatory process. One of the key mediators of the inflammatory process is TGF-beta1 and our recent studies have focused on TGF-beta-1 homozygous null mice in which the gene for TGF- beta-1 has been inactivated as a model of autoimmune-like pathology similar to Sjogren's Syndrome. Moreover, beyond its immunoregulatory role, TGF-beta-1 is considered essential to healing and tissue repair because of its growth and synthetic influences on mesenchymal cells. In this regard, we have taken advantage of TGF-beta-1-gene targeted mutant mice which over-express TGF-beta-1 (TGF-beta-1 transgenics) or in which TGF-beta-1 has been inactivated (TGF-beta-1-/-; null mutation) or partially inactivated (TGF-beta-1+/-; null mutation heterozygotes), to explore the role of this peptide in a model of fibropathology. Schistosomiasis mansoni, an extracellular parasite, which is a major cause of hepatic fibrosis in many developing countries, triggers a granulomatous inflammatory reaction in response to its eggs that lodge in the liver. The persistent granulomatous response leads to prolonged matrix synthesis and hepatic fibrosis during which TGF-beta-1 is produced. Matrix production and fibrosis in response to natural infection with S.mansoni worms exhibited distinct profiles in TGF-beta-1 gene targeted mice, consonant with their levels of TGF-beta-1. Although fibrotic manifestations appear dependent on TGF-beta-1 levels, fibrosis is not eliminated in the absence of TGF-beta-1, nor overwhelming in mice overexpressing this fibrogenic peptide. These observations emphasize the multifactorial nature of the signals involved in the complex pathophysiology of this and other fibrotic diseases. Nonetheless, as a link in the cytokine cascade, TGF-beta-1 represents a potential target for novel therapies in fibrotic disorders. Another effector molecule in inflammation and repair is nitric oxide (NO), the synthesis of which is regulated by TGF-beta.